The syndromes of reduced sensitivity to thyroid hormone

Abstract

Background: Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified.

Scope of review: The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases.

Major conclusions: Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH.

General significance: Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling.

Figure 1

Regulation of TH supply, metabolism and genomic action. (A) Central feedback control that regulates the amount of TH in blood. (B) Intracellular metabolism of TH, regulating TH bioactivity. (C) Genomic action of TH. For details see text. CBP/P300, cAMP-binding protein/general transcription adaptor; TFIIA and TFIIB, transcription intermediary factor II, A and B; TBP, TATA-binding protein; TAF, TBP-associated factor. (Modified from Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):277–305.)

Figure 2

Schematic representation of the DNE mechanism: In the absence of T₃, occupancy of TRE by TR heterodimers (TR-RXR) or dimers (TR-TR) suppresses transactivation through association with a corepressor (CoR). (A) T₃-activated transcription mediated by TR-RXR heterodimers involves the release of the CoR and association with coactivators (CoA) as well as (B) the removal of TR dimers from TRE releases their silencing effect and liberates TREs for the binding of active TR-RXR heterodimers. The DNE of a mutant TR (mut TR), that does not bind T₃, can be explained by the inhibitory effect of mut TR-containing-dimers and heterodimers that occupy TRE. Thus, T₃ is unable to activate the mut TR-RXR heterodimer (A') or release TREs from the inactive mut TR homodimers (B'). (Modified from Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14:348–399.)

Figure 3

Location of natural mutations in the TRβ molecule associated with RTH. TOP PORTION: Schematic representation of the TRβ and its functional domains for interaction with TREs (DNA-binding) and with hormone (T₃-binding). Their relationship to the three clusters of natural mutations is also indicated. TRβ2 has 15 more residues than TRβ1 at the amino-terminus. BOTTOM PORTION: The location of the 170 different mutations detected and their frequencies in the total of 459 unrelated families (published and our unpublished data). Amino acids are numbered consecutively starting at the amino terminus of the TRβ1 molecule according to the consensus statement of the First International Workshop on RTH [134]. "Cold regions" are areas devoid of mutations associated with RTH.

Figure 4

Responses to the administration of L-T₃ in subjects with RTH, with and without mutations in the TRβ gene and in a normal individual. The hormone was given in three incremental doses, each for 3 days. Results are shown at baseline and after each dose of L-T₃ in patients with RTH in the presence (left) or absence (right) of a TRβ gene mutation, and the unaffected mother of the patient with nonTR-RTH (center). (A) TSH responses to TRH stimulation. (B) Responses of peripheral tissues. Note the stimulation of ferritin and sex hormone binding globulin (SHBG) and the suppression of cholesterol and creatine kinase (CK) in the normal subject. Responses in affected subjects, with or without a TRβ gene mutation, were blunted or paradoxical. (Modified from Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):277–305.)

Figure 5

Location of mutations in the MCT8 molecule associated with THCMTD Shown by vertical lines are 58 known mutant MCT8 proteins and their frequency in 80 families (published and our unpublished data). Horizontal lines indicate the mutations with deletions of large regions. Numbering is consecutive, starting at the amino terminus of the 613 amino acid human molecule. The 12 TMDs are indicated in blue. Loops predicted to be outside the cell are indicated by an O and those inside the cell, by an I.

Figure 6

(A) Thyroid function tests in several families with MCT8 deficiency studied in the authors’ laboratory. Grey regions indicate the normal range for the respective test. Hemizygous males (M) are represented as red squares, heterozygous carrier females (F), as green circles and unaffected members of the families, as blue triangles (N). With the exception of TSH, mean values of iodothyronines in carrier females are significantly different than those in affected males and normal relatives. (B) Thyroid function tests in subjects from 4 families with SBP2 deficiency studied in the authors’ laboratory. Grey regions indicate the normal range for the respective test. Affected individuals are represented as red squares and unaffected members of the families, as blue circles. (Modified from Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):277–305.)

Figure 7

Tissue T₃ content Mct8KO and Wt mice and its corresponding effect. A. T₃ content and D1 enzymatic activity in liver. B. T₃ content and D2 enzymatic activity in brain. Data from Mct8KO mice are represented as grey bars and those from Wt littermates are in open bars. ** p-value <0.01, *** p-value <0.001. S.A., specific activity. (Modified from Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):277–305.)

Figure 8

Schematic representation of the components involved in Sec incorporation that are central to the synthesis of selenoproteins. Elements present in the mRNA of selenoproteins are an in frame UGA codon and Sec incorporation sequence (SECIS) element, a stem loop structure located in the 3’UTR (untranslated region). SBP2 binds SECIS and recruits the Sec-specific elongation factor (EFSec) and Sec-specific tRNA (tRNA^Sec) thus resulting in the recoding of the UGA codon and Sec incorporation.

Figure 9

In-vivo and in-vitro studies in subjects with SBP2 deficiency. (A) In-vivo studies: Serum TSH and corresponding serum T₄ and T₃ levels, before and during the oral administration of incremental doses of L-T₄ and L-T₃. Note the higher concentrations of T₄ required to reduce serum TSH in the affected subjects; (B) In-vitro studies of deiodinase 2 in cultured skin fbroblasts: Baseline and stimulated D2 activity is significantly lower in affected individuals. There is significant increase of DIO2 mRNA with dibutyryl cyclic adenosine monophosphate [(db)-cAMP), in both unaffected and affected (*p <0.001) while there are no significant differences in baseline (db)-cAMP stimulated DIO2 mRNA in affected versus the unaffected. (Modified from Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):277–305.)